Recombinant Human ACE2-Fc : A promising therapy for SARS-CoV2 infection

P.K, S.; Shandil, R. K.; Suresh, P.; Biswas, K.; Rudramurthy, G. R.; Nanjegowda, N. C.; Kumaraswamy, B.; Battula, N. P.; Chowdhury, S. D.; Sinha, S.; Dutta, S.; Dhar, S. K.; Narayanan, S.; Das, M.

doi:10.1101/2022.07.30.501940

bioRxiv · 10.1101/2022.07.30.501940

Recombinant Human ACE2-Fc : A promising therapy for SARS-CoV2 infection

P.K, S.·Shandil, R. K.·Suresh, P.·Biswas, K.·Rudramurthy, G. R.·Nanjegowda, N. C.·Kumaraswamy, B.·Battula, N. P.·Chowdhury, S. D.·Sinha, S.·Dutta, S.·Dhar, S. K.·Narayanan, S.·Das, M.

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Abstract

SARS-CoV2 entry is mediated by binding of viral spike-protein(S) to the transmembrane Angiotensin-Converting Enzyme-2 (ACE2) of the host cell. Thus, to prevent transmission of disease, strategies to abrogate the interaction are important. However, ACE2 cannot be blocked since its normal function is to convert the Angiotensin II peptide to Angiotensin(1-7) to reduce hypertension. This work reports a recombinant cell line secreting soluble ACE2-ectopic domain (MFcS2), modified to increase binding and production efficacy and fused to human immunoglobulin-Fc. While maintaining its enzymatic activity, the molecule trapped and neutralized SARS CoV2 virus in vitro with an IC50 of 64 nM. In vivo, with no pathology in the vital organs, it inhibited the viral load in lungs in SARS-CoV2 infected Golden-Syrian-hamster. The Intravenous pharmacokinetic profiling of MFcS2 in hamster at a dose of 5 mg/Kg presented a maximum serum concentration of 23.45 {micro}g/mL with a half-life of 29.5 hrs. These results suggest that MFcS2 could be used as an effective decoy based therapeutic strategy to treat COVID19. This work also reports usage of a novel oral-cancer cell line as in vitro model of SARS-Cov2 infection, validated by over expressing viral-defence pathways upon RNA-seq analysis and over-expression of ACE2 and TMPRSS upon growth in hyperglycaemic condition.

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P.K, S., Shandil, R. K., Suresh, P., Biswas, K., Rudramurthy, G. R., Nanjegowda, N. C., Kumaraswamy, B., Battula, N. P., Chowdhury, S. D., Sinha, S., Dutta, S., Dhar, S. K., Narayanan, S., Das, M.. 2022-08-01. Recombinant Human ACE2-Fc : A promising therapy for SARS-CoV2 infection. https://doi.org/10.1101/2022.07.30.501940

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